Complications of diabetes Mellitus are numerous and manifested by a wide range of pathological conditions including abnormalities in the response to painful stimuli. The role of endogenous opioid peptides in mediation of antinociceptive effect in animal and human has been documented. We have found that streptozotocin (STZ)-induced diabetes in rats resulted in a significant increase in the hot plate latency test which developed gradually over 6-7 weeks period post induction of diabetes. this analgesic response was associated with several-folds increase of free Met-enkephalin (ME) in plasma and various brain regions. The object of these studies is to determine the neurochemical basis that regulate the level of the endogenous ME in diabetes. We hypothesize that the high level of free ME is a result of an abnormal activation of the releasing process of ME from the larger pool (precursor) and/or decrease in its turn over rate. To test this hypothesis, we will determine: (1) Whether the high level of free ME in plasma, spinal cord and brain regions in diabetes is due to enhanced ME release and/or decrease in its degradation, (2) if the high circulating level of glucose in diabetes plays a role in increasing the level of ME, (3) whether the increase in free ME level is modulated indirectly by another endogenous neurotransmitter (i.e., DA) as a result of diabetes, (4) if diabetes alters the kinetic of free ME and/or its immediate precursor (cryptic form), (5) whether controlling the diabetic state with chronic insulin administration prevents, ameliorates or reverse such alteration in the level, and distribution of ME similar to that of the non-diabetes control rat. In addition to testing this hypothesis, we also plan to determine the time course for the development of such changes after the induction of diabetes as well as the schedule of insulin treatment that correct such problems. These studies should provide insight into the factors that regulate the level of ME in diabetes and indirectly, the analgesic response as one of the pathophysiological condition associated with this disease. Should the diabetic state produce an alteration in the releasing and/or turnover rate of ME, these results might provide a rational basis for drug treatment or drug interaction involving the antinociceptive system of diabetic patients.